Fat-laden macrophages modulate lobular inflammation in nonalcoholic steatohepatitis (NASH)
| Autor: | Cristina Bozzola, Salvatore Sutti, Irene Locatelli, Maurizio Parola, Aastha Jindal, Claudia Paternostro, Emanuele Albano, S. Bruzzì |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Pathology medicine.medical_specialty Clinical Biochemistry Nitric Oxide Synthase Type II Inflammation Monocytes Pathology and Forensic Medicine Mice Non-alcoholic Fatty Liver Disease Annexin Nonalcoholic fatty liver disease medicine Animals Antigens Ly Humans CXCL10 Molecular Biology Triglycerides Annexin A1 Homeodomain Proteins CD11b Antigen Arginase biology Tumor Necrosis Factor-alpha Macrophages Tumor Suppressor Proteins Monocyte Alanine Transaminase medicine.disease Fibrosis Interleukin-12 Diet Interleukin-10 Chemokine CXCL10 Mice Inbred C57BL Cytoskeletal Proteins medicine.anatomical_structure Liver Integrin alpha M Disease Progression biology.protein Steatohepatitis medicine.symptom |
| Popis: | Nonalcoholic steatohepatitis (NASH) is characterized by extensive hepatic monocyte infiltration and monocyte-derived macrophages have an important role in regulating the disease evolution. However, little is known about the functional changes occurring in liver macrophages during NASH progression. In this study, we investigated phenotypic and functional modifications of hepatic macrophages in experimental NASH induced by feeding C57BL/6 mice with a methionine–choline deficient (MCD) diet up to 8 weeks. In mice with steatohepatitis liver F4/80-positive macrophages increased in parallel with the disease progression and formed small clusters of enlarged and vacuolated cells. At immunofluorescence these cells contained lipid vesicles positive for the apoptotic cell marker Annexin V suggesting the phagocytosis of apoptotic bodies derived from dead fat-laden hepatocytes. Flow cytometry revealed that these enlarged macrophages expressed inflammatory monocyte (CD11b, Ly6C, TNF-α) markers. However, as compared to regular size macrophages the enlarged sub-set was characterized by an enhanced production of arginase-1 and of the anti-inflammatory mediators IL-10 and annexin A1. Similar vacuolated macrophages producing annexin A1 were also evident in liver biopsies of NASH patients. In mice with NASH, the accumulation of enlarged F4/80+ cells paralleled with a decline in the expression of the macrophage M1 activation markers iNOS, IL-12 and CXCL10, while the levels of M2 polarization markers arginase-1 and MGL-1 were unchanged. Interestingly, the lowering of IL-12 expression mainly involved the macrophage sub-set with regular size. We conclude that during the progression of NASH fat accumulation within liver macrophages promotes the production of anti-inflammatory mediators that influence hepatic inflammatory responses. |
| Databáze: | OpenAIRE |
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